Orphanin FQ (also known as nociceptin; abbreviated N/OFQ) is a brain peptide with close sequence homology to the opioid peptide, dynorphin. N/OFQ is present in brain during development and is widely distributed in discrete brain regions in the adult. It is synthesized as a precursor protein, pN/OFQ, that also contains other peptides with potential bioactivity; nocistatin (NST) and OFQ2. N/OFQ has selective affinity for an orphan opioid receptor (NOP receptor) that has high sequence homology to the kappa opioid receptor. Neural functions of N/OFQ are not well understood. Generally, N/OFQ inhibits all neurons expressing NOP receptors. Activation of NOP receptors reduces the release of many neurotransmitters, including dopamine, glutamate, and GABA. The N/OFQ-NOP receptor system appears to play a role in the neural response to injury. Initial results suggest a probable effect of endogenously released N/OFQ or related peptides in reducing neural cell survival after seizures and after chemical injury to discrete neuronal populations. The goals of this proposal are first to identify the major products of N/OFQ gene expression under resting conditions, and to determine if the relative concentrations of the bioactive products change after seizures and other stimuli to N/OFQ gene expression. Secondly, we will evaluate mechanisms that appear to be involved in N/OFQ-mediated facilitation of neurotoxicity following seizures or exposure to neurotoxins and drugs of abuse (e.g. methamphetamine) that damage mid-brain dopamine neurons. These studies should contribute to our understanding of neural damage following seizures or exposure to toxins or drugs, and may be relevant to an understanding of Parkinson's Disease. Studies on the potential protective effects of NOP receptor antagonists in seizure states and after exposure to neurotoxic agents might lead to the development of novel neuroprotective therapies.